Professional Interests

SYNDROMIC DEAFNESS AND CONNEXIN HEMICHANNEL DYSFUNCTION

Permanent childhood deafness occurs with an incidence of ~1.5 cases per 1000 live births. Approximately 30% of deaf children have cognitive impairment due to the loss of functional interactions among the sensory systems. Although there are a number of genes associated with inherited deafness, mutation of the GJB2 gene encoding the Cx26 gap junction (GJ) protein is the most common. In addition to cognitive impairment and slowed development, there is growing evidence that some Cx26 mutations are linked to developmental cerebellar anomalies. Our studies are currently focusing on a subset of GJB2 mutations that lead to syndromic forms of deafness in which sensorineural hearing loss is accompanied by severe, inflammatory skin disorders, such as keratitis-ichthiosis-deafness (KID) syndrome. Some KID syndrome mutations result in fatality due to uncontrollable sepsis. The underlying basis of KID syndrome and other forms of syndromic deafness appears to be aberrantly behaving hemichannels, a relatively new mechanism identified among Cx-related disorders. Cx hemichannels do not participate in the formation of intercellular GJ channels, but rather remain undocked and function as large, ion channels in the plasma membrane. Mutant hemichannels have been described to behave in a "leaky" manner leading to compromised cell function and cell death. We use a combination of molecular, biophysical and imaging approaches to investigate the mechanisms by which Cx hemichannels are dysfunctional. A collaborative project uses keratinocytes isolated from transgenic mice carrying KID mutations under an inducible promoter. The mice develop normally in the absence of induction, but when induced they develop hair loss, skin lesions and show hyperproliferation of the epidermis. Maintained induction is ultimately proves fatal. We are also working towards a mouse model to study KID in the cochlea. Explants of the organ of Corti show robust GJB2 expression in the support cells that are vital for sensory transduction. Studies using such native tissues should help establish genotype-phenotype correlations for syndromic deafness and lead to strategies for treatment. Overall, we hope to also shed light on a growing list of disorders ascribed to hemichannel dysfunction that includes atherosclerosis, stroke, neuropathy and congenital cataractogenesis.